The acquisition of migratory and invasive properties by tumor cells is a central and often fatal step in neoplastic disease progression. While normal, non-transformed cells have strict growth factor and adhesive requirements for motility, malignant cells have overcome these requirements through multiple mechanisms including gain of function oncogene mutations, growth factor receptor overexpression and/or constitutive deregulation of extracellular matrix degrading enzymes. Not coincidentally, many solid cancers also possess very low oxygen tensions (Koong et al., 2000b; Buchler et al., 2004).
Hypoxia can induce Macrophage migration inhibitory factor (MIF) expression. It has been demonstrated that MIF expression is increased in pre-malignant, malignant and metastatic tumors. Breast, prostate, colon, brain, skin and lung-derived tumors have all been shown to contain significantly higher levels of MIF message and protein than their non-cancerous cell counterparts. MIF expression closely correlates with tumor aggressiveness and metastatic potential, possibly suggesting an important contribution to disease severity by MIF. MIF has been indirectly implicated in tumor growth and progression by stimulating tumor-dependent stromal processes such as neovascularization. As well, MIF has been implicated in macrophage and lymphocyte activation and survival and may play a role in inflammatory disorder progression.
Thus, certain aggressive tumors appear to possess an important functional requirement for MIF in maintaining optimal growth and progression. Further, MIF may be important in the progression of inflammatory disorders. MIF can therefore be a desirable target for development of therapeutics for the treatment of cancer. As such, there is presently an unmet need for therapeutic molecules that specifically target MIF and modulate one or more biological activities of MIF for the treatment of cancers and inflammatory disorders.